This invention relates to 2,3,4,5-tetrahydro-1H-3-benzazepines having anti-psychotic activity, and also to the synthesis of .alpha.-substituted-arylacetamides, especially fused-ring nitrogen heterocycles, in particular dihydroindoles, 1,2,3,4-tetrahydroisoquinolines and 1,2,3,4,5,6-hexahydro-3-benzazocines, and most particularly 2,3,4,5-tetrahydro-1H-3benzazepines.
Dihydroindoles, 1,2,3,4-tetrahydroisoquinolines, 1,2,3,4,5,6-hexahydro-3-benzazocines, and particularly 2,3,4,5-tetrahydro-1H-3-benzazepines are known to have useful pharmacological properties. For example, U.S. Pat. Nos. 3,393,192, 3,609,138, 4,011,319, 4,284,555 and 4,477,378, and British Patent Specification no. 1,118,688, all describe 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines having various activities described as antibacterial effects, central nervous system effects and hypotensive effects.
Weinstock et al. in Drugs of the Future, Vol. 10, No. 8, pp. 645-697 (1985) discuss the profound effect that 1-phenyl substituents have on the dopaminergic activity of certain types of benzazepines; see in particular Table II on page 666.
European Patent Application No. 83105610.6 (published as 0,096,838) discloses certain 1-aryloxy-2,3,4,5-tetrahydro-1H-3-benzazepines optionally having alkoxy substituents in the 7- and/or 8-position; these compounds are disclosed as having utility in treating depression.
U.S. Pat. No. 5,015,639 describes and claims 2,3,4,5-tetrahydro-1H3-benzazepines lacking a 1-phenyl group but having instead a variety of 1-substituents including a group of the formula ##STR1## wherein m is 0 or 1, and each of the groups R.sup.9, which can be the same or different, is a hydrogen atom or an alkyl, alkoxy, alkoxyalkyl, aralkyl or aryl group. These compounds have good anti-dopaminergic activity, and in particular show surprising selectivity for the D-1 subclassification of dopaminergic receptors. Iorio et al., Pharmacol Exp. Ther. (1983), 226, page 462, and Iorio et al. in Neurobiology of Central D.sub.1 -Dopamine Receptors, pages 1-14 in Advances in Experimental Medicine and Biology 204, Eds. Creese and Breese, Plenum, New York, 1986, have also evaluated the effects of benzazepines on dopamine receptors. Charifson et al., J. Med. Chem. (1988), 31, pages 1941-1946, have similarly evaluated 1,2,3,4-tetrahydroisoquinolines.
International Application No. PCT/US 91/04046 describes and claims (inter alia) compounds having the structural formula A ##STR2## and the pharmaceutically acceptable salts thereof, wherein: R.sup.10 represents H, C.sub.1-4 -alkyl, allyl or cyclopropylmethyl;
R.sup.11 represents C.sub.3-8 -cycloalkyl or C.sub.5-8 -cycloalkenyl; PA1 R.sup.12 represents C.sub.1-4 -alkyl; and PA1 R.sup.13 represents (inter alia,) R.sup.12, H or R.sup.12 CO. PA1 which comprises the reaction of an arylacetamide having at least one hydrogen atom and preferably two hydrogen atoms on the .alpha.-carbon atom, wherein the nitrogen atom carries no hydrogen atoms, with a strong base in an inert aprotic organic solvent; PA1 followed by reaction, in the presence of a zerovalent transition metal catalyst, with a compound of the formula EQU R.sup.4 --X (I) PA1 and X is a leaving group, e.g., --OSO.sub.2 F or an activated ester group. PA1 R.sup.4 is a 1-cycloalkenyl group; PA1 R is an alkyl, alkenyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl group; PA1 and Y is an oxygen atom or H.sub.2 ; PA1 and their non-toxic salts with bases when R.sup.1 is or contains a hydroxy group; PA1 and their non-toxic acid addition salts when Y is H.sub.2. PA1 n is 0,1,2,3 or 4 (but preferably 1 or 2); PA1 each R.sup.la is independently selected from alkyl, alkenyl, alkoxy, alkenyloxy, cycloalkyl, nitro, halogen, polyfluoroloweralkyl, phenyl and phenoxy, or two groups R.sup.1a in adjacent positions optionally form an alkylenedioxy group or a fused benzene ring, and the phenyl or phenoxy group or the fused benzene dng is optionally substituted by a group selected from alkyl, alkenyl, alkoxy, alkenyloxy, cycloalkyl, nitro, halogen, polyfluoroloweralkyl, and alkylenedioxy; PA1 R.sup.4 is selected from aromatic groups, 1-alkenyl groups and 1-cycloalkenyl groups; PA1 and R is an alkyl, alkenyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl group. PA1 alkenyl (including the alkenyl portion of alkenyloxy)--represents a straight or branched hydrocarbon chain having at least one carbon-to-carbon double bond and having from 2 to 10, preferably from 2 to 6, carbon atoms; it should especially be noted that, when R.sup.4 in the compound of the formula R.sup.4 X is an alkenyl group, the group X is attached to said alkenyl group at a carbon atom forming the carbon-carbon double bond; PA1 alkynyl (especially the alkynyl portion of alkynyloxy)--represents a straight or branched hydrocarbon chain having at, least one carbon-to-carbon triple bond and having from 2 to 10, preferably from 2 to 6, carbon atoms; PA1 alkyl (including the alkyl portions of alkoxy, cycloalkylalkyl and aralkyl)--represents a straight or branched, saturated hydrocarbon chain having from 1 to 10 carbon atoms but preferably a lower alkyl group having from 1 to 6 carbon atoms; PA1 alkylene (in particular the alkylene portion of-alkylenedioxy)--represents a straight or branched, saturated hydrocarbon chain having from 1 to 6, preferably from 1 to 3, carbon atoms, with the two free valencies on the same carbon atom or on different ones; PA1 aryl (including the aryl portion of aryloxy and aralkyl groups)--represents phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl and indanyl; PA1 cycloalkenyl--represents a carbocyclic group having from 5 to 8, preferably 5 or 6, carbon atoms and one, two or three carbon-to-carbon double bonds in the ring (but preferably only one), and optionally bearing one or two lower alkyl substituents; it should especially be noted that, when R.sup.4 in the compound of the formula R.sup.4 X is a cycloalkenyl group, the group X is attached to said cycloalkenyl group at a carbon atom bearing a carbon-carbon double bond; PA1 cycloalkyl (including the cycloalkyl portion of cycloalkylalkyl)--represents a saturated carbocyclic ring having from 3 to 8, preferably from 5 to 7 carbon atoms; PA1 halogen--represents fluorine, chlorine, bromine and iodine; PA1 aromatic heterocyclic (heteroaryl)--represents a cyclic group having at least one O, S and/or N interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic group having from 2 to 14, preferably from 2 to 8, especially from 2 to 5, carbon atoms, e.g., 2-, 3-or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6-[1,2,4-triazinyl], 3-or 5-[1,2,4-thiadiazolyl], 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5- 6-or 7-(1-substituted)-indolyl, 2-, 4- or 5-oxazolyl, etc. Preferred heteroaryl groups are 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2-, 4- or 5-imidazolyl, and 7-(1-substituted)-indolyl (where the 1-substituent is for example methyl); PA1 substituted phenyl--represents a phenyl group in which 1 to 3 hydrogen atoms thereof are replaced by the same or different substituents independently chosen from alkyl, alkenyl, alkoxy, alkenyloxy, nitro, halogen, trifluoromethyl, cyano, cycloalkyl, alkynyloxy, or wherein two hydrogen atoms in adjacent positions are selected from alkylenedioxy; PA1 polyfluoroloweralkyl--represents a straight or branched alkyl group containing 1 to 4 carbon atoms wherein at least two hydrogen atoms have been replaced by fluorine atoms, e.g., C.sub.2 F.sub.5, CH.sub.3 CF.sub.2, and CF.sub.3 CH.sub.2, and especially CF.sub.3. PA1 1,3,4,5-Tetrahydro-2H-3-benzazepin-2-ones: PA1 2,3,4,5-Tetrahydro-1H-3-benzazepines (by reduction and O-demethylation of the (R,S)-compounds listed above): PA1 Resolved enantiomers of 2,3,4,5-tetrahydro-1H-3-benzazepines: PA1 n is 1 or 2; PA1 each R.sup.1 is independently selected from lower alkoxy, hydroxy, halogen, polyfluoroloweralkyl, nitro and phenoxy; PA1 R.sup.4 is a 1-cycloalkenyl group; PA1 R is a lower alkyl group; PA1 and Y is H.sub.2. PA1 R.sup.6 is a lower alkyl group, preferably a methyl group, or a hydrogen atom; PA1 R.sup.7 is selected from lower alkoxy, hydroxy, CF.sub.3 and halogen; PA1 and R.sup.8 is selected from lower alkoxy, hydroxy and halogen; PA1 Preferably, R.sup.7 is halogen and R.sup.8 is hydroxy. Most preferably, R.sup.7 is chlorine.
These compounds are useful in the treatment of psychoses, depression, pain and hypertension.
Ciufolini et al., Tetrahedron Letters 1987, Vol. 28 No. 2, 171-174, have described a 'model' intramolecular arylation of 2-[2-(2-iodophenyl)ethyl]-indan.alpha.-1,3-dione with tetrakis(triphenylphosphine)palladium(0), to yield a spiro(indane-1,3-dione-2,1'-indane), in experiments on the synthesis of Friedricamycin. In further studies of prototype substrates and also of substrates used in studies of the synthesis of Friedricamycin, Ciufolini et al., J. Org. Chem. [Communications]1988, 53,4149-4151, have described intramolecular arylations of 'soft' enolates (i.e., enolates having a pK.sub.a &lt;15) catalyzed by zerovalent palladium. A phenyl halide moiety in one part of the molecule was condensed with an enol in another part of the molecule to provide a benzo-fused five- or six-membered homocyclic or heterocyclic ring; but compounds with a fused four-membered ring could not be produced. One example in Table I therein shows the formation of an indolone by intramolecular condensation of an N-methyl-N-(2-ethoxycarbonylpropanoyl)-2-iodoanilide. In an adaptation of this method, Piers et al., J. Org. Chem. 1990, 55, 3454-3455, have disclosed a five -membered ring annulation method based on Pd(0)-catalyzed intramolecular coupling of a vinyl iodide function with an enolate anion function; in this method, the enolate anion was in a saturated five- or six-membered ring.
A modification of the reaction disclosed by Ciufolini et al. was published by Negishi et al., J. Am. Chem. Soc., 1989, 111,8018-8020. Using compounds analogous to those which, in the hands of Ciufolini et al, had failed to produce compounds with a fused four-membered ring, they were able to effect a cyclization in the presence of carbon monoxide under pressure: the product was a ketone with its carbonyl group (provided by the carbon monoxide) in a fused five-membered ring. They were similarly able to produce analogous ketones with the carbonyl group in a fused six- or seven-membered ring, and even effect the cyclization on non-cyclic intermediates to produce unfused cyclopentenones.
In all these reactions catalyzed by a zerovalent metal, the enolate is generally stabilized by an adjacent activating group (such as ester-carbonyl, keto-carbonyl or nitrile).